A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

Regenerative therapies for femoral head necrosis in the past two decades: a systematic review and network meta-analysis.

BACKGROUND: Regenerative techniques combined with core decompression (CD) are commonly used to treat osteonecrosis of the femoral head (ONFH). However, no consensus exists on regeneration therapy combined with CD that performs optimally. Therefore, we evaluated six regenerative therapies combined with CD treatment using a Bayesian network meta-analysis (NMA). METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science databases. Six common regeneration techniques were categorized into the following groups with CD as the control group: (1) autologous bone graft (ABG), (2) autologous bone graft combined with bone marrow aspirate concentrate (ABG + BMAC), (3) bone marrow aspirate concentrate (BMAC), (4) free vascular autologous bone graft (FVBG), (5) expanded mesenchymal stem cells (MSCs), and (6) platelet-rich plasma (PRP). The conversion rate to total hip arthroplasty (THA) and progression rate to femoral head necrosis were compared among the six treatments. RESULT: A total of 17 literature were included in this study. In the NMA, two of the six treatment strategies demonstrated higher response in preventing the progression of ONFH than CD: MSCs (odds ratio [OR]: 0.098, 95% confidence interval [CI]: 0.0087-0.87) and BMAC (OR: 0.27, 95% CI: 0.073-0.73). Additionally, two of the six treatment strategies were effective techniques in preventing the conversion of ONFH to THA: MSCs (OR: 0.062, 95% CI: 0.0038-0.40) and BMAC (OR: 0.32, 95% CI: 0.1-0.074). No significant difference was found among FVBG, PRP, ABG + BMAC, ABG, and CD in preventing ONFH progression and conversion to THA (P > 0.05). CONCLUSIONS: Our NMA found that MSCs and BMAC were effective in preventing ONFH progression and conversion to THA among the six regenerative therapies. According to the surface under the cumulative ranking value, MSCs ranked first, followed by BMAC. Additionally, based on our NMA results, MSCs and BMAC following CD may be necessary to prevent ONFH progression and conversion to THA. Therefore, these findings provide evidence for the use of regenerative therapy for ONFH.

Targeted sequencing identifies risk variants in 202 candidate genes for neurodevelopmental disorders.

With the continuous deepening of genetic research on neurodevelopmental disorders (NDDs), more patients have been identified the causal or candidate genes. However, it is still urgent needed to increase the sample size to confirm the associations between variants and clinical manifestations. We previously performed molecular inversion probe sequencing of autism spectrum disorder (ASD) candidate genes in 1543 ASD patients. In this study, we used the same method to detect de novo variants (DNVs) in 665 NDD patients with intellectual disability (ID) and/or epilepsy (EP) for genetic analysis and diagnosis. We compared findings from ID/EP and ASD patients to improve our understanding of different subgroups of NDDs. We identified 72 novel variants and 39 DNVs. A totally of 5.71 % (38/665) of the patients were genetically diagnosed by this sequencing strategy. ID/EP patients demonstrated a higher prevalence of likely gene disruptive DNVs in ASD genes than the healthy population. Regarding high-risk genes, SCN1A and CKDL5 were more frequently mutated in ID/EP patients than in ASD patients. Our data provide an overview of the mutation burden in ID/EP patients from the perspective of high risk ASD genes, indicating the differences and association of NDDs subgroups.

Efficacy of Chinese herbal formula Kai-Xin-San on rodent models of depression: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS, or Happy Feeling Powder), a typical Chinese herbal prescription, is frequently used for treating depression by the multi-level and multi-target mechanism. AIM OF THE STUDY: To systematically investigate the efficacy and safety of KXS on depression in preclinic trials. MATERIALS AND METHODS: We independently searched for preclinical animal studies of KXS on depression from inception to June 28, 2022, using electronic databases, e.g., PUBMED. The measurements were performed to assess the outcomes of behavioral tests. RESULTS: This systematic review and meta-analysis included twenty-four studies and 608 animals. A remarkable effect of KXS in depression behavioral tests, including sucrose consumption test (SMD: 2.36, 95% CI: (1.81, 2.90); Z = 8.49, P < 0.00001)., forced swimming test (MD = -60.52, 95% CI: (-89.04, -31.99); Z = 4.16, P < 0.0001), rearing times (MD=4.48, 95% CI: (3.39, 5.57); Z = 8.05, P < 0.00001) and crossing times (MD = -33.7, 95% CI: (25.74, 41.67); Z = 8.29, P < 0.00001) in the open field test, showing KXS's excellent efficiency in improving depressive-like symptoms of animals. CONCLUSIONS: Our meta-analysis showed KXS remarkably relieved animals' depressive-like symptoms, providing evidence that KXS can be a promising drug candidate for depression treatment.

A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression.

PURPOSE: To systematically assess the evidence of efficacy and safety of the use of ketamine and esketamine for patients with treatment-resistant depression (TRD) with suicidal ideation (SI). METHODS: We independently searched for clinical trials from inception to January 2023 using electronic databases, e.g., PubMed and EMBASE. A systematic review and meta-analysis were performed to assess SI scores of depression rating scales, which were regarded as the outcomes. RESULTS: A total of five independent double-blind, placebo controlled randomized clinical trials (RCTs) are eligible for inclusion. Four of the studies used ketamine as an intervention and one used esketamine as an intervention. Three hundred ninety-one patients with TRD were included (the intervention group with ketamine or esketamine is 246, and the control group is 145). No statistically significant interaction between the subscales of suicide ideation (SMD = - 0.66, 95% CI (- 1.61, 0.29); Z = 1.36, P = 0.17) and antidepressant effects (SMD = - 0.99, 95% CI (- 2.33, 0.34); Z = 1.46, P = 0.15) based on the results of ketamine and esketamine, compared with placebo groups. CONCLUSION: This meta-analysis suggested that esketamine and ketamine have failed to reduce suicidal ideation in patients with TRD. Further studies are desirable to confirm the effects of ketamine and esketamine in TRD patients.

Adeno-associated virus-mediated gene therapy for rare pediatric neurogenetic diseases: Current status and outlook. / è ºç›¸å ³ç— æ¯’ä»‹å¯¼çš„åŸºå› æ²»ç–—åœ¨å„¿ç«¥ç¥žç»é—ä¼ ç½•è§ç— ä¸­åº”ç”¨çš„çŽ°çŠ¶ä¸Žå±•æœ›.

Rare pediatric neurogenetic diseases always have early onset, no specific therapy, high mortality, and pose a severe risk to the health and survival of children. Adeno-associated virus (AAV)-mediated gene therapy, a type of disease-modifying therapy, provides a new option for the treatment of rare pediatric neurogenetic diseases and represents a significant advancement in the field. Currently, the US Food and Drug Administration (FDA) and the European Medicines Association (EMA) have approved AAV-mediated gene therapy medications for treating spinal muscular atrophy, aromatic L-amino acid decarboxylase deficiency, and Duchenne muscular dystrophy. Numerous preclinical and clinical trial research findings from recent years indicate that AAV-mediated gene therapy has a promising future in treating genetic disorders. The quick approval process for rare diseases medications may bring hope for the treatment of children with rare neurogenetic diseases. AAV-mediated gene therapy is an emerging technology with certain risks and challenges. It is necessary to establish a standardized regulatory system and a sound long-term follow-up system to evaluate the efficacy and safety of gene therapy.

First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa.

BACKGROUND: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. METHODS: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. RESULTS: In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. CONCLUSION: SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn, identifier is CTR20211082.

Effects of sugar beet pectin on the pasting, rheological, thermal, and microstructural properties of wheat starch.

The effects of addition of sugar beet pectin (SBP) on the pasting, rheological, thermal, and microstructural properties of wheat starch (WS) were investigated. Results revealed that SBP addition significantly increased the peak viscosity, trough viscosity, breakdown value, final viscosity, and setback value of WS, whereas decreased the pasting temperature. SBP raised the swelling power (from 13.44 to 21.32 g/g) and endothermic enthalpy (ΔH, from 8.17 to 8.98 J/g), but decreased the transparency (from 9.70 % to 1.37 %). Regarding rheological properties, WS-SBP mixtures exhibited a pseudo-plastic behavior, and SBP enhanced the viscoelasticity, but decreased the deformability. Particle size distribution analysis confirmed that SBP promoted the swelling of WS granules. Fourier-transform infrared spectroscopy results suggested that the interactions between SBP and WS did not involve covalent bonding, and the formation of ordered structure was inhibited by SBP addition. Additionally, scanning electron microscopy observation found that the gel network of WS-SBP mixtures became more irregular, pore size gradually decreased, and the wall became thinner as the SBP concentration increased. These results indicated that SBP is a promising non-starch polysaccharide that can enhance the processing properties of WS.

Impact of Internet development on carbon emission efficiency under carbon neutral target: evidence from global 58 economies.

With the introduction of economy carbon neutral target policies one after another worldwide, the carbon emission reduction actions of economies around the world have become a hot topic attracting international attention. Meanwhile, the role of the Internet in energy saving and emissions reduction in economies around the world is also becoming more prominent. However, for now, there is still a lack of in-depth research on the impact and role relationship between Internet development and global economy carbon emission efficiency. Therefore, based on the availability of data, this study used the Malmquist index based on game intersection to measure and analyze carbon emission efficiency based on 58 economies around the world that proposed carbon neutrality targets between 2000 and 2019. The study used a spatial econometric model to explore the impact of Internet development on carbon emission efficiency. The objective was to provide a policy reference for high-, medium-, and low-income economies worldwide to achieve their carbon neutrality targets as soon as possible. The results of the study showed that carbon emission efficiency was closely linked to economic development level in economies around the world, that the gap between the development levels of high- and low-Internet-connected economies is gradually widening, that Internet development significantly improved carbon emission efficiency, that levels of economic and financial development played a mediating role in the relationship between Internet development and carbon emissions efficiency, and that the level of urbanization played a moderating role in the relationship between Internet development and carbon emissions efficiency. Exploring the influence and the mechanism of action between Internet development and carbon emission efficiency will contribute to early achievement of global carbon neutrality targets in all economies.

Effect of flumetsulam alone and coexistence with polyethylene microplastics on soil microbial carbon and nitrogen cycles: Elucidation of bacterial community structure, functional gene expression, and enzyme activity.

Flumetsulam (FLU) is a new class of broad-spectrum herbicides. With the widespread use of plastic products, polyethylene (PE) microplastics (MPs) may remain in the soil. It is possible for these two novel contaminants to co-exist in the soil environment. In the present study, we used brown soil as the test soil and determined the toxicity of FLU at 0.05, 0.5 and 2.5 mg kg-1 alone and in combination with PE MPs (1%) on soil microorganisms. The obtained results demonstrated that the exposure of FLU and FLU+MPs had an inhibitory effect on the numbers of bacteria and fungi. In addition, FLU and FLU+MPs caused changes in the relevant functional bacterial genera, favored nitrogen fixation and denitrification, and promoted soil carbon fixation, but inhibited nitrification. Compared to FLU exposure alone, exposure to FLU+MPs gave rise to significant differences in soil bacterial community composition, but did not affect carbon and nitrogen cycling. The integrated biomarker response results indicated that the toxicity of FLU and FLU+MPs to soil microorganisms increased with increasing concentrations of FLU. The present experiment clarified the toxicological effects of co-exposure of FLU and MPs on microorganisms and filled the toxicological data gap of FLU.

Are PFBS, PFHxS, and 6:2FTSA more friendly to the soil environment compared to PFOS? A new insight based on ecotoxicity study in soil invertebrates (Eisenia fetida).

As alternatives to perfluorooctane sulfonate (PFOS) with shorter carbon chains or lower proportion of fluorine atoms, perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and 6:2 fluorotelomer sulfonic acid (6:2FTSA) have been detected in various environmental media. However, it is unclear whether the toxicity of these alternatives is lower than that of PFOS. Therefore, this study investigated the toxicity and differences in PFBS, PFHxS, 6:2FTSA, and PFOS (0.2 mg/kg) after 56 d of exposure using the common invertebrate Eisenia fetida in soil as the test organism. The results showed that although PFOS, PFBS, PFHxS, and 6:2FTSA induced oxidative stress and apoptosis in earthworms and led to developmental and reproductive toxicity in terms of comprehensive toxicity, PFHxS > PFOS > PFBS >6:2FTSA. To reveal the mechanisms underlying the differences in toxicity between the alternatives and PFOS, we conducted molecular docking and transcriptomic analyses. The results indicated that, unlike PFOS, PFBS, and PFHxS, 6:2FTSA did not cause significant changes in antioxidant enzyme activity at the molecular level. Furthermore, PFOS exposure caused disorder in the nervous and metabolic systems of earthworms, and PFHxS disrupted energy balance and triggered inflammatory responses, which may be important reasons for the higher toxicity of these compounds. In contrast, exposure to 6:2FTSA did not result in adverse transcriptomic effects, suggesting that 6:2FTSA exerted the least molecular-scale toxicity in earthworms. The results of this study provide new insights into the environmental safety of using PFBS, PFHxS, and 6:2FTSA as alternatives to PFOS.

[Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review]. / SYNGAP1åŸºå› å˜å¼‚ç›¸å ³å¸¸æŸ“è‰²ä½“æ˜¾æ€§æ™ºåŠ›éšœç¢5型8ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. METHODS: A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University. RESULTS: The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy. CONCLUSIONS: Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.

A Novel Ensemble Fault Diagnosis Model for Main Circulation Pumps of Converter Valves in VSC-HVDC Transmission Systems.

The intelligent fault diagnosis of main circulation pumps is crucial for ensuring their safe and stable operation. However, limited research has been conducted on this topic, and applying existing fault diagnosis methods designed for other equipment may not yield optimal results when directly used for main circulation pump fault diagnosis. To address this issue, we propose a novel ensemble fault diagnosis model for the main circulation pumps of converter valves in voltage source converter-based high voltage direct current transmission (VSG-HVDC) systems. The proposed model employs a set of base learners already able to achieve satisfying fault diagnosis performance and a weighting model based on deep reinforcement learning that synthesizes the outputs of these base learners and assigns different weights to obtain the final fault diagnosis results. The experimental results demonstrate that the proposed model outperforms alternative approaches, achieving an accuracy of 95.00% and an F1 score of 90.48%. Compared to the widely used long and short-term memory artificial neural network (LSTM), the proposed model exhibits improvements of 4.06% in accuracy and 7.85% in F1 score. Furthermore, it surpasses the latest existing ensemble model based on the improved sparrow algorithm, with enhancements of 1.56% in accuracy and 2.91% in F1 score. This work presents a data-driven tool with high accuracy for the fault diagnosis of main circulation pumps, which plays a critical role in maintaining the operational stability of VSG-HVDC systems and satisfying the unmanned requirements of offshore flexible platform cooling systems.

p-AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells.

OBJECTIVE: Small extracellular vesicle (sEV)-mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs. SUBJECTS AND METHODS: Fifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p-AKT/vacuolar protein sorting-associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells. RESULTS: The size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B. CONCLUSION: Downregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs.

Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease.

BACKGROUND: Icariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. METHODS: The PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. RESULTS: The study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aß via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca2+, and PI3K/Akt signaling. ICA exhibits neuroprotective properties by inhibiting neuronal apoptosis through the suppression of ER stress in AD mice, potentially linked to NF-κB, MAPK, ERK, and PERK/Eif2α signaling pathways. Moreover, ICA may safeguard neurons by attenuating mitochondrial oxidative stress injury. ICA can also enhance learning, memory, and cognition by improving synaptic structure via regulation of the PSD-95 protein. Furthermore, ICA can mitigate neuroinflammation by inactivating microglial activity through the upregulation of PPARγ, TAK1/IKK/NF-κB, and JNK/p38 MAPK signaling pathways. CONCLUSION: This study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD.

TransFNN: A Novel Overtemperature Prediction Method for HVDC Converter Valves Based on an Improved Transformer and the F-NN Algorithm.

Appropriate cooling of the converter valve in a high-voltage direct current (HVDC) transmission system is highly significant for the safety, stability, and economical operation of a power grid. The proper adjustment of cooling measures is based on the accurate perception of the valve's future overtemperature state, which is characterized by the valve's cooling water temperature. However, very few previous studies have focused on this need, and the existing Transformer model, which excels in time-series predictions, cannot be directly applied to forecast the valve overtemperature state. In this study, we modified the Transformer and present a hybrid Transformer-FCM-NN (TransFNN) model to predict the future overtemperature state of the converter valve. The TransFNN model decouples the forecast process into two stages: (i) The modified Transformer is used to obtain the future values of the independent parameters; (ii) the relation between the valve cooling water temperature and the six independent operating parameters is fit, and the output of the Transformer is used to calculate the future values of the cooling water temperature. The results of the quantitative experiments showed that the proposed TransFNN model outperformed other models with which it was compared; with TransFNN being applied to predict the overtemperature state of the converter valves, the forecast accuracy was 91.81%, which was improved by 6.85% compared with that of the original Transformer model. Our work provides a novel approach to predicting the valve overtemperature state and acts as a data-driven tool for operation and maintenance personnel to use to adjust valve cooling measures punctually, effectively, and economically.

Desipramine enhances the stability of atherosclerotic plaque in rabbits monitored with molecular imaging.

Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL-induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM-mediated apoptosis in plaque improves stability in vivo. In this study, rabbits with abdominal aorta balloon injury and a 12-week high-cholesterol diet (HCD) were used to simulate an atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL. We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar in plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in the Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, the uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration, and plaque instability. The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in a rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring of atherosclerotic disease and evaluation of anti-atherosclerotic therapy.

A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases.

U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an indispensable pre-mRNA splicing factor in the early process of splicing. Recently, U2AF2 was reported as a novel candidate gene associated with neurodevelopmental disorders. Herein, we report a patient with a novel presumed heterozygous missense variant in the U2AF2 gene (c.603G>T), who has a similar clinical phenotype as the patient reported before, including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum. We reviewed the phenotypic and genetic spectrum of patients with U2AF2-related neurological diseases, both newly diagnosed and previously reported. To investigate the possible pathogenesis, EBV-immortalized lymphoblastoid cells were derived from the peripheral blood obtained from the patient and control groups. Furthermore, according to the results of WB, RT-PCR, Q-PCR, and cDNA sequencing of RT-PCR products, the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del). Cell Counting Kit-8 (CCK-8) and cell cycle detection demonstrated that the variant c.603G>T inhibited the proliferation of patient lymphocyte cells compared with the control group. This study is aimed at expanding the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases and investigating the potential effects. This is the first report of the possible pathogenesis of a U2AF2 gene pathogenic variant in a patient with neurodevelopmental diseases and shows that a novel presumed missense variant in the U2AF2 gene causes exon skipping.

The effect of TiO2NPs on cloransulam-methyl toxicity to earthworm (Eisenia fetida).

Cloransulam-methyl is a new herbicide and has broad application prospect. However, the effect of cloransulam-methyl on earthworm have yet to be clarified. As more and more titanium dioxide nanoparticles (TiO2NPs) enter the soil, cloransulam-methyl and TiO2NPs have a risk of co-exposure, but the effect of TiO2NPs on cloransulam-methyl toxicity is unknown. In the study, the ecotoxicity of cloransulam-methyl (0.1, 1 mg kg-1) on earthworm and the effect of TiO2NPs (10 mg kg-1) on cloransulam-methyl toxicity was investigated after exposure for 28 and 56 d. Exposure tests showed cloransulam-methyl and cloransulam-methyl + TiO2NPs promoted the accumulation of reactive oxygen species, malondialdehyde and 8-hydroxydeoxyguanosine, increased the activities of superoxide dismutase and catalase, resulted in lipid peroxidation and DNA damage. Besides, the results at the genetic level showed cloransulam-methyl and cloransulam-methyl + TiO2NPs altered the expression of physiologically-related genes, which demonstrated that cloransulam-methyl and cloransulam-methyl + TiO2NPs induced oxidative stress and cell apoptosis, and disturbed the normal reproduction in earthworm. The results of comprehensive toxicity comparison indicated cloransulam-methyl and TiO2NPs co-exposure has higher toxicity compared to cloransulam single exposure. Our results suggest that TiO2NPs can enhance the toxicity of cloransulam-methyl on Eisenia fetida in terms of oxidative stress, cell apoptosis and reproduction aspects. Based on above studies, it is of great importance for evaluating the risk of cloransulam-methyl co-exposure with TiO2NPs in soil.

Development toxicity and cytotoxicity of pyroxsulam on embryos and adults of zebrafish (Danio rerio).

Pyroxsulam is a typical triazolopyrimidine sulfonamide herbicide, which plays a vital role in weed control for wheat production. Previous studies on pyroxsulam have mainly focused on weed resistance, control effects, and soil microorganisms, however, research on aquatic ecotoxicity is lacking. This study evaluated the toxicity of pyroxsulam in zebrafish embryos (120 h) and adults (14 and 28 d). Chronic exposure to pyroxsulam (0.2, 2, and 10 µg L-1) reduced reactive oxygen species (ROS) content in embryos but increased ROS content in adults. Pyroxsulam caused lipid peroxidation and DNA damage in embryos and adults. The expression of p53, bcl-2/bax, and caspase 3/8/9 indicated that pyroxsulam inhibited apoptosis in embryos but induced apoptosis in adults. By calculating integrated biomarker response, apoptosis was more readily affected than oxidative damage in embryos and adults. The toxicity of pyroxsulam increased with increasing concentration, however, with increasing exposure time, the toxicity of pyroxsulam to adults decreased. Pyroxsulam exerted toxic effects on zebrafish at different life stages (embryos and adults), and different stages had different toxicity. These results indicate that in future studies on the toxicity of pyroxsulam to zebrafish, different life stages (embryos and adults) need to be studied. The present study evaluated the toxicity of environmentally relevant concentrations of pyroxsulam to zebrafish embryos and adults, providing worthy data for assessing its effects on aquatic ecosystems.